Medico-Legal Controversies in the Management of Preterm Labour:
“Off-Label” Medicines - Saj Shah
Medico-Legal Controversies in the Management of Preterm Labour: “Off-Label”
Medicines
Saj Shah
Director of Pharmaceutical Consultancy
Epalan Limited
London, England
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This session is going to be on the medical/legal controversies in the
management of preterm labour. I am actually going to be looking at the legal
issues relating to the use of off-label medicines. What I mean by off-label
medicines is that they are the same as off-license medicines where licensed
medicines are used outside the terms of their product license.
What I want to do is present a small experiment to you. The experiment is to
evaluate the absorption of two different forms of the same drug. Now this
requires a bit of imagination from you. Imagine that there are two drug addicts;
drug addict A, and drug addict B, both receiving treatment for a substance
misuse and their dependence. The treatment that they are receiving is by opioid
analgesic, such as bupenorphine. Bupenorphine is licensed to be administered as
an oral tablet.
In the case of drug addict A, the doctor administers the oral tablet, as a whole
tablet. In the case of drug addict B, the doctor crushes the tablet because drug
addict B is giving him a bit of trouble and he wants to reduce the supervised
consumption time. So he crushes the tablet. Now let’s see what actually happens
in this circumstance.
There you have drug addict A, and drug addict B. A whole tablet and a crushed
tablet, this is not bupenorphine; this is vitamin C for all those who are
concerned.
This is a simple experiment but it shows that by crushing a tablet you can alter
the pharmacological properties of a particular medicine. Crushing the tablet can
make the absorption into the bloodstream that much more quickly, altering the
therapeutic effect and increasing the incidence of side effects, by crushing the
tablet and taking it outside the terms of its product license, its off-label
use.
Now, the issues with off-label use are not only pharmacological in nature, there
are legal implications to consider, particularly when there are licensed
alternatives available. This is what my session is going to concentrate on.
Over the last 30 or so years there has been a concerted effort to develop
effective tocolytic agents, and two, particularly in Europe, have emerged as the
successors to the beta agonists, atosiban and nifedipine. Now, as Professor Khan
said in his presentation, that there is at the moment, no head to head
comparison of the two drugs, atosiban and nifedipine, yet the general view is
that they are equivalent in efficacy. So, what are the differences?
Well, these are the obvious differences; the cost, it is one of the major
differences, the route of administration between the two drugs, licensing.
Atosiban is licensed for preterm labour, nifedipine is not. As Professor Khan
dealt with that adequately, I will not go into the differences in the studies
being carried out, except to say that at the moment, I understand, there have
not been any major studies on safety of nifedipine use in preterm labour. With
safety in mind you may have all read the recent BJOG report reporting safety
issues with nifedipine in pregnancy. But apart from safety concerns there are
two main issues that get left out and people forget about, and that is the risk
management implications and the medical liability issues with regards to
off-label medicine use.
Now, everyone in their practise, be it health care professionals, lawyers,
recognise the importance of controlling risk. More so for doctors, in this day
and age with public knowledge at its highest, it is no longer sufficient to
actually learn and improve only when things go wrong. You actually have to be
proactive and not reactive.
Medical litigation over the last ten or so years has been increasing
dramatically and it is no surprise that avoiding medical malpractice law suits
has become a huge priority for all doctors worldwide. Insurance premiums for
medical litigation are skyrocketing as well, particularly in the US and Europe.
Now it has been reported that off-label drug use is likely to become the junk
science litigation bonanza of the 21st century. Couple this with the fact that
statistics show that the most likely area of healthcare practice that a claim of
negligence, or a claim by a patient, is going to come to is in the field of
obstetrics and gynaecology. This makes a very distressing sound bite. Claimant
lawyers are avoiding science altogether. What they are trying to do is convince
the courts that off-label drug use is inherently dangerous. It is untested and
it is independent of any scientific or biological evidence in itself.
Defending an allegation of negligence is not only costly; it is actually
personally insulting to you. It is emotionally hurtful, it damages your
practice, it damages your ego, defending is time consuming and distracting, and
it attracts a lot of media coverage.
To actually understand the legal and risk management implications of off-label
drug use, we need to briefly look at how medicines are actually licensed and
look at the systems and the procedures that are in place, that control the
safety, efficacy and quality of medicines.
Since the thalidomide tragedy in the 1960s, most developed countries around the
world introduced medical laws regulating the safety and efficacy testing of
medicines. In Europe, no medicine can be placed on the market without a
marketing authorisation, formerly called product license, issued by the relevant
authority, or the European Medicines Evaluation Authority. The purpose of
licensing is to ensure that medicines are actually checked for their safety,
efficacy and quality. The medicines are rigorously tested before they can even
become candidates for submission to the regulatory process.
I just want to show you this diagram, which was produced by the Association of
the British Pharmaceutical Industry. This really summarises the development of a
drug in a nutshell, showing how a drug moves from the test tube, to approval,
into general usage. The ABPI have reported that it takes an average between 10
to 12 years to develop a new medicine to the standards of quality and efficacy
required by the law. And during this period only one to two medicines in every
10,000 that are evaluated actually get on to receiving a product license. And
the product license itself is specific to a particular condition.
What happens when a defect in a licensed product causes harm to a patient? In
most European countries if a defect in a licensed medicine causes harm to a
patient, the manufacturer of that licensed product will be exposed to two main
areas of liability. All European countries have an established tradition of tort
liability, liability in negligence, which considers the fault in a person’s
conduct in order to achieve damages for a particular patient. In this case a
manufacturer will be liable in negligence for negligent design or negligent
manufacture or negligent marketing.
There is also another scheme, the strict liability scheme where the patient or
the consumer does not actually have to prove fault. This is under the EC
directive on the liability for defective products, which most European countries
have implemented, and the countries that have not implemented the directive
already have quite strong product liability national laws.
Practically no country in the world has formal legislation forbidding the use of
off-label medicines. Medical laws are drafted to provide doctors and clinicians
the clinical freedom and the clinical discretion to prescribe medicines as they
see fit. But what happens when an off-label medicine causes harm to a patient?
Well, in this case the manufacturer of that medicine, the manufacturer of the
licensed medicine will assume no liability. They will escape liability by
claiming that the defect and the harm were not caused by their tablet. Something
was altered in their tablet.
There is also another important defence that manufacturers have in such a case
and this is the Informed Intermediary Doctrine. Anyone from the US will
appreciate that this is being used quite a lot in the US by manufacturers. It is
yet untested by the courts in Europe. But under the Informed Intermediary
Doctrine the manufacturer gets round their duty to warn consumers directly by
providing adequate information to their prescribers, the informed intermediary.
What is this adequate information? It is the Summary of Product Characteristics
of each and every medicine, the SPC, which is the basis of information for
health care professionals on how to use the product safely, effectively and
within the terms of its product license. The product license is not actually
published, but the SPC summarises what that particular medicine is licensed for.
We saw earlier that there are pharmacological implications. Now the legal
implications are very simple.
Liability for harm for use of an off-label medicine falls down to the
prescriber. The prescriber increases their own responsibility for prescribing
off-label medicines. They carry the burden of the patient’s welfare and they may
be called upon to justify actions if damage results from off-label medicine use.
Okay, so those are the legal implications, but how will a clinician, be exposed
to medical liability or tortious liability in negligence? I actually want to
look at this in slightly more detail.
I am not going to go into the legal systems of different countries around the
world but there are obviously two different types, the civil law for continental
European countries where the laws is codified in civil codes, and the common
law, which is used in the UK and US, which is law based on cases before judges
in courts. Although there are different legal systems around the world, when it
comes to proving medical negligence and medical liability, there are actually
common elements that a patient needs to prove, which are the same in all legal
systems around the world although the terminology may differ.
There are three essential elements that a patient needs to prove in order to
succeed in a claim against a doctor for negligence. The first as you all know
would be that the doctor actually owed a duty of care to the patient. Now, this
is established in most countries around the world. It is established law that
doctors owe a duty of care to their patients. The second element is that the
doctor breached their duty of care by failing to reach the standard of care
required by the law. This can differ from country to country. In the UK, in
England, the standard of care of a consultant obstetrician is that of an
ordinary skilled consultant obstetrician exercising and professing to have that
special skill. A doctor in England is not negligent if he acts in accordance
with the practice accepted at the time as proper by a responsible body of
medical opinion. Ah! So you can prescribe a medicine off-label if you have a
responsible body of medical opinion, your other colleagues, stating that this is
fine to do. Well, the courts went further. They said, “Well no, it is for the
courts to decide in the UK”. The responsible body of medical opinion has to have
a logical basis. It has to involve the weighing of risks and benefits in order
to reach a defensible conclusion.
I want to give you an example of the standard of care in Germany, which is the
standard of an experienced physician in their respective medical specialty. The
standard of care in the Netherlands is the standard of care expected of a
conscientious doctor, acting in accordance with professional standards.
Once breach of duty has been proven the next element to actually prove is that
that breach of duty actually caused the patient injury, loss or damage, which
was foreseeable and avoidable.
So, if we take the UK as an example, the law in the UK, am I really saying that
a doctor in England could be exposed to a claim in negligence for prescribing
nifedipine in preterm labour? Well, if that nifedipine use causes harm to the
patient, and there is a licensed alternative, the answer to that question could
be yes. It is going to be difficult for any doctor to convince a court that with
a logical analysis of the situation weighing the risks and the benefits of
treatment, it was better for the patient’s welfare, and in the patient’s best
interest to use an off-label medicine over a licensed alternative which has been
submitted to the gold standard independent peer scrutiny of the licensing
process. Now, this is quite controversial stuff and it is yet untested,
particularly in Europe.
What is more plausible is failure to provide adequate information. A patient can
bring a claim against a doctor to state that they breached their duty to warn
and provide enough information about a particular treatment. Informed consent is
a prerequisite to any medical intervention. A patient has the right to refuse or
halt treatment as they see fit. Traditionally in England when a patient claimed
or sued a doctor for negligence for failing to provide adequate information, the
doctor had quite a strong defence. This was because it was for the patient to
prove that had they been given adequate information they would not have
consented to the treatment. This is quite a high burden for the patient to
prove.
As of October last year, the whole legal situation with regards to consent in
England changed. The case of Chester v. Afshar went all the way to the House of
Lords, which is the highest court in the UK. This was a case dealing with
consent and lack of adequate information. The judges in the House of Lords
rejected this traditionally strong defence for doctors and opted for the
patient. What they actually considered was that a patient should have a remedy
against a doctor where he had breached his duty to the patient by failing to
allow her to make a reasonably informed decision as to whether to consent to a
particular treatment. You can see that this ruling actually places a great
burden on all clinicians, particularly in the UK, taking extreme care in their
consenting process to ensure that they have advised a patient adequately and
informed them about a particular treatment to make sure that they have valid
consent.
The duty to warn is also recognised, believe it or not, in most developed
countries in the world. The decision in Chester is actually quite new for
England but it is very similar to the legal situations in most continental
European countries, where the doctor has the burden of proving that he either
fulfilled his duty to inform the patient, or that even if the patient was
adequately informed, she would have gone ahead with the treatment in any event.
This is quite a high burden for doctors to prove. Some civil codes go as far as
to specifically state that a health care provider has a positive obligation to
inform patients about other possible types of treatment.
So, for prescribers using off-label medicines when there are licensed
alternatives available, this could mean that consent may not be valid unless the
prescriber gives the patient enough information for that patient to make a
reasonably informed decision whether to proceed with that medicine or not.
What is enough information? Well, ask yourselves if you were the patient; what
would you like to know? The risks and benefits associated with the use of
nifedipine, the fact that there is a licensed alternative available? Would you
also like to make sure that your patient actually knows what is meant by
off-label drug use, the fact that it has not actually been subjected to the
rigorous testing that licensed medicines have been? Certainly in England now
this, the consenting process, particularly with regards to off-label medicines,
has now completely changed and the consenting process now will involve providing
all this added information.
So, it is all about sensible prescribing. Prescribing off-label medicines, when
there are licensed alternatives available, has the potential to endanger public
safety and breach professional and legal requirements. I just want to quote the
General Medical Council’s Guidance, the regulator in England for doctors. The
GMC guidance on off-label medicine use states that, “Off-label medicine use
should only be considered if it is imperative to continue treatment and no
licensed equivalent is available. Or, when there is a licensed alterative
available, the doctor must be satisfied that the off-label medicine suits the
patient’s needs better.”
The overriding issue as you all know with off-label medicine use is whether the
off-label medicine will affect the patient. Its use has to be in the best
interest in the patient. Prescribing off-label medicines for the convenience of
the health care team, or on grounds of costs, unfortunately is not a defence to
claim in negligence and is generally unacceptable by courts. So, the doctor has
the legal and professional responsibility for prescribing off-label medicines.
You need to obtain appropriate consent, which again, will involve the patient
being in a position where they can make a reasonably informed decision. This
will mean giving them the full details of the fact that nifedipine is being used
off-label, and that there is a licensed alternative, unfortunately the safety
profile is unknown because it is untested, and explaining exactly what off-label
medicine actually means.
But to also cover yourself even more, you need to record the consenting process
in the medical records because the general view by courts, say seven, ten years
down the line, when a claim does come about is, if it is not in the medical
records, it was not done. So make accurate records of the consenting process and
the reasons for using a particular medicine off-label.
At the moment the philosophy appears to be let doctors prescribe as they see
fit. Now, unfortunately for you, claimant lawyers want to change this
philosophy. How they are trying to change this philosophy is actually that they
feel that obstetric drug regulation is failing, and they want to change it by
regulating drugs through litigation. This is not an elegant solution but this is
how we are now going. The legal systems around the world have offered another
type of regulation. This is drug regulation by public education and personal
autonomy.
Although costs of a particular medicine are a justifiable concern, they must be
viewed in the context of public safety and also professional and legal
liability. All clinicians need to be aware of their responsibilities when
prescribing off-label medicines, particularly to ensure that adequate consent is
obtained, and recorded in the patient records.
With regards to safety, many may actually argue that there is no evidence of
harm from the use of nifedipine in preterm labour. The way I like to think of
evidence of harm is that the absence of evidence of harm is not the same as
evidence of absence of harm.
Thank your for listening.
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